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Otolaryngologic Clinics of North America Dec 2021Ototoxicity refers to damage to the inner ear that leads to functional hearing loss or vestibular disorders by selected pharmacotherapeutics as well as a variety of... (Review)
Review
Ototoxicity refers to damage to the inner ear that leads to functional hearing loss or vestibular disorders by selected pharmacotherapeutics as well as a variety of environmental exposures (eg, lead, cadmium, solvents). This article reviews the fundamental mechanisms underlying ototoxicity by clinically relevant, hospital-prescribed medications (ie, aminoglycoside antibiotics or cisplatin, as illustrative examples). Also reviewed are current strategies to prevent prescribed medication-induced ototoxicity, with several clinical or candidate interventional strategies being discussed.
Topics: Aminoglycosides; Anti-Bacterial Agents; Cisplatin; Ear, Inner; Humans; Ototoxicity
PubMed: 34774227
DOI: 10.1016/j.otc.2021.08.007 -
The Lancet. Child & Adolescent Health Feb 2020Despite ototoxicity being a prevalent consequence of cisplatin chemotherapy, little guidance exists on interventions to prevent this permanent and progressive adverse... (Review)
Review
Despite ototoxicity being a prevalent consequence of cisplatin chemotherapy, little guidance exists on interventions to prevent this permanent and progressive adverse event. To develop a clinical practice guideline for the prevention of cisplatin-induced ototoxicity in children and adolescents with cancer, we convened an international, multidisciplinary panel of experts and patient advocates to update a systematic review of randomised trials for the prevention of cisplatin-induced ototoxicity. The systematic review identified 27 eligible adult and paediatric trials that evaluated amifostine, sodium diethyldithiocarbamate or disulfiram, systemic sodium thiosulfate, intratympanic therapies, and cisplatin infusion duration. Regarding systemic sodium thiosulfate, the panel made a strong recommendation for administration in non-metastatic hepatoblastoma, a weak recommendation for administration in other non-metastatic cancers, and a weak recommendation against its routine use in metastatic cancers. Amifostine, sodium diethyldithiocarbamate, and intratympanic therapy should not be routinely used. Cisplatin infusion duration should not be altered as a means to reduce ototoxicity. Further research to determine the safety of sodium thiosulfate in patients with metastatic cancer is encouraged.
Topics: Adolescent; Antineoplastic Agents; Child; Cisplatin; Female; Hearing Loss; Humans; Male; Neoplasms; Ototoxicity; Prognosis; Randomized Controlled Trials as Topic; Survival Rate; Thiosulfates
PubMed: 31866182
DOI: 10.1016/S2352-4642(19)30336-0 -
Biomedicine & Pharmacotherapy =... Jan 2023Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss. The main etiologies are stria vascularis... (Review)
Review
Administration of cisplatin, a common chemotherapeutic drug, has an inevitable side effect of sensorineural hearing loss. The main etiologies are stria vascularis injury, spiral ganglion degeneration, and hair cell death. Over several decades, the research scope of cisplatin-induced ototoxicity has expanded with the discovery of the molecular mechanism mediating inner ear cell death, highlighting the roles of reactive oxygen species and transport channels for cisplatin uptake into inner ear cells. Upon entering hair cells, cisplatin disrupts organelle metabolism, induces oxidative stress, and targets DNA to cause intracellular damage. Recent studies have also reported the role of inflammation in cisplatin-induced ototoxicity. In this article, we preform a narrative review of the latest reported molecular mechanisms of cisplatin-induced ototoxicity, from extracellular to intracellular. We build up a signaling network starting with cisplatin entering into the inner ear through the blood labyrinth barrier, disrupting cochlear endolymph homeostasis, and activating inflammatory responses of the outer hair cells. After entering the hair cells, cisplatin causes hair cell death via DNA damage, redox system imbalance, and mitochondrial and endoplasmic reticulum dysfunction, culminating in programmed cell death including apoptosis, necroptosis, autophagic death, pyroptosis, and ferroptosis. Based on the mentioned mechanisms, prominent therapeutic targets, such as channel-blocking drugs of cisplatin transporter, construction of cisplatin structural analogues, anti-inflammatory drugs, antioxidants, cell death inhibitors, and others, were collated. Considering the recent research efforts, we have analyzed the feasibility of the aforementioned therapeutic strategies and proposed our otoprotective approaches to overcome cisplatin-induced ototoxicity.
Topics: Humans; Cisplatin; Antineoplastic Agents; Hair Cells, Auditory; Ototoxicity; Cochlea; Apoptosis
PubMed: 36455457
DOI: 10.1016/j.biopha.2022.114045 -
Journal of Cellular and Molecular... Oct 2020Ferroptosis is a recently recognized form of non-apoptotic cell death caused by an iron-dependent accumulation of lipid hydroperoxides, which plays important roles in a...
Ferroptosis is a recently recognized form of non-apoptotic cell death caused by an iron-dependent accumulation of lipid hydroperoxides, which plays important roles in a wide spectrum of pathological conditions. The present study was aimed to investigate the impact of ferroptosis on cisplatin-induced sensory hair cell damage. Cell viability was determined by Cell Counting Kit-8 and lactase dehydrogenase assays. The reactive oxygen species (ROS) levels were evaluated by 2,7-Dichlorodi-hydrofluorescein diacetate (DCFH-DA) and MitoSox-Red staining. Mitochondrial membrane potential (MMP) was measured by tetramethylrhodamine methyl ester (TMRM) staining. Lipid peroxidation, intracellular and mitochondrial iron were detected by Liperfluo, C11-BODIPY , FerroOrange and Mito-FerroGreen, respectively. We found that cisplatin treatment not only markedly augmented ROS accumulation, decreased the MMP, but increased lipid peroxidation and iron accumulation in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. Of note, treatment with the specific ferroptosis inhibitor ferrostatin-1 could effectively abrogate the cisplatin-induced toxicity and subsequent cell death. Specifically, the improvement of mitochondrial functions is important mechanisms for protective action of ferroptosis inhibitor against cisplatin-induced damages in HEI-OC1 cells. Moreover, inhibition of ferroptosis significantly protected murine cochlear hair cells against cisplatin damage. In addition, treatment murine cochlear hair cells with ferroptosis inducer, RSL3, significantly exacerbated cisplatin-induced damage, which could be alleviated by ROS inhibitor N-acetyl-L-cysteine. Collectively, our study indicated that ferroptosis inhibition could alleviate the cisplatin-induced ototoxicity via inactivation of lipid peroxide radical and improvement of mitochondrial function in hair cells.
Topics: Aldehydes; Animals; Carbolines; Cell Line; Cell Survival; Cisplatin; Cyclohexylamines; Cytoprotection; Ferroptosis; Hair Cells, Auditory; Iron; Iron Overload; Membrane Potential, Mitochondrial; Mice, Inbred C57BL; Ototoxicity; Phenylenediamines; Reactive Oxygen Species
PubMed: 32929878
DOI: 10.1111/jcmm.15839 -
Cancer Jun 2016Ototoxicity is a well-established toxicity associated with a subgroup of antineoplastic therapies that includes platinum chemotherapy, radiation or surgery involving the... (Review)
Review
Ototoxicity is a well-established toxicity associated with a subgroup of antineoplastic therapies that includes platinum chemotherapy, radiation or surgery involving the ear and auditory nerve, and supportive care agents such as aminoglycoside antibiotics and loop diuretics. The reported prevalence of ototoxicity in patients who have received potentially ototoxic therapy ranges from 4% to 90% depending on factors such as age of the patient population, agent(s) used, cumulative dose, and administration techniques. The impact of ototoxicity on subsequent health-related and psychosocial outcomes in these patients can be substantial, and the burden of morbidity related to ototoxic agents is particularly high in very young children. Considerable interindividual variability in the prevalence and severity of ototoxicity has been observed among patients receiving similar treatment, suggesting genetic susceptibility as a risk factor. The development and testing of otoprotective agents is ongoing; however, to the author's knowledge, no US Food and Drug Administration-approved otoprotectants are currently available. Prospective monitoring for ototoxicity allows for comparison of auditory outcomes across clinical trials, as well as for early detection, potential alterations in therapy, and auditory intervention and rehabilitation to ameliorate the adverse consequences of hearing loss. Cancer 2016;122:1647-58. © 2016 American Cancer Society.
Topics: Age Factors; Antineoplastic Agents; Ear; Ear Diseases; Genetic Predisposition to Disease; Hearing Loss; Humans; Medical Illustration; Neoplasms; Postoperative Complications; Prevalence; Radiation Injuries; Radiotherapy; Tinnitus; Vertigo
PubMed: 26859792
DOI: 10.1002/cncr.29779 -
Cancer Jan 2022Platinum-containing chemotherapy is often used to treat children with cancer. Although it is a very effective medication, unfortunately, it causes permanent hearing loss...
Platinum-containing chemotherapy is often used to treat children with cancer. Although it is a very effective medication, unfortunately, it causes permanent hearing loss in more than one-half of the children who receive it. In this issue of Cancer, an article by Meijer and colleagues shows that very young children are affected early on in their treatment and suggests that the younger the child the more frequently their hearing should be tested during treatment. This proposal is a real challenge for oncology centers and families practically, emotionally, and socioeconomically. The findings are provocative but equally stimulating and encouraging; hopefully, they will lead to a new standard of multidisciplinary care for children receiving platinum chemotherapy.
Topics: Antineoplastic Agents; Carboplatin; Child; Child, Preschool; Cisplatin; Hearing Loss; Humans; Ototoxicity
PubMed: 34490622
DOI: 10.1002/cncr.33847 -
Theranostics 2020Hair cells in the inner ear have been shown to be susceptible to ototoxicity from some beneficial pharmaceutical drugs, such as aminoglycosides and cisplatin. Thus,...
Hair cells in the inner ear have been shown to be susceptible to ototoxicity from some beneficial pharmaceutical drugs, such as aminoglycosides and cisplatin. Thus, there is great interest in discovering new targets or compounds that protect hair cells from these ototoxic drugs. Epigenetic regulation is closely related to inner ear development; however, little is known about epigenetic regulation in the process of ototoxic drugs-induced hearing loss. : In this study, we investigated the role of protein arginine methyltransferase 6 (PRMT6) in aminoglycoside- and cisplatin-induced hair cell loss by using EPZ020411, a selective small molecule PRMT6 inhibitor, in neonatal mouse cochlear explants and in C57BL/6 mice. We also took advantage of the HEI-OC1 cell line to evaluate the anti-apoptosis effects of PRMT6 knockdown on cisplatin-induced ototoxicity. Apoptotic cells were identified using cleaved caspase-3 staining and TUNEL assay. The levels of reactive oxygen species (ROS) were evaluated by DCFH-DA and cellROX green staining. The mitochondrial membrane potential (ΔΨm) were determined by JC-1, TMRM, and rhodamine 123 staining. : We found that EPZ020411 significantly alleviated neomycin- and cisplatin-induced cell apoptosis and increased hair cell survival. Moreover, pretreatment with EPZ020411 could attenuate neomycin- and cisplatin-induced hearing loss . Mechanistic studies revealed that inhibition of PRMT6 could reverse the increased expression of caspase-3 and cytochrome translocation, mitochondrial dysfunction, increased accumulation of ROS, and activation of cell apoptosis after cisplatin injury. : Our findings suggested that PRMT6 might serve as a new therapeutic target to prevent hearing loss caused by aminoglycoside- and cisplatin-induced ototoxicity by preventing ROS formation and modulating the mitochondria-related damage and apoptosis.
Topics: Animals; Anti-Bacterial Agents; Apoptosis; Cell Line; Cisplatin; Enzyme Inhibitors; Hair Cells, Auditory; Hearing Loss; Mice; Mice, Inbred C57BL; Mitochondria; Neomycin; Protein-Arginine N-Methyltransferases; Reactive Oxygen Species
PubMed: 31903111
DOI: 10.7150/thno.37362 -
Journal of Audiology & Otology Apr 2018Ototoxicity is the pharmacological adverse reaction affecting the inner ear or auditory nerve, characterized by cochlear or vestibular dysfunction. The panorama of... (Review)
Review
Ototoxicity is the pharmacological adverse reaction affecting the inner ear or auditory nerve, characterized by cochlear or vestibular dysfunction. The panorama of drug-induced hearing loss has widened over last few decades. Although ototoxic medications play an imperative role in modern medicine, they have the capacity to cause harm and lead to significant morbidity. Evidence has shown early detection of toxicity through prospective ototoxicity monitoring allows for consideration of treatment modifications to minimize or prevent permanent hearing loss and balance impairment. Although many ototoxicity monitoring protocols exist, their practicality is questionable due to several factors. Even though the existing protocols have proven to be effective, certain lacunae in practice have been encountered due to discrepancies among recommended protocols. Implementation of these protocols is mostly held back due to the incapacitated status of the patient. The choice of early ototoxicity identification techniques is still debatable due to variables such as high degree of sensitivity, specificity and reliability, less time consumption and less labour-intensive to the patient. Hence, the diagnosis and effective treatment of ototoxicity is challenging, even today. A stringent protocol with more practicality encompassing all elements aimed at profiling the effects of ototoxicity is greatly needed. This review describes an efficient application of ototoxicity monitoring and treatment protocol as an attempt to reduce the challenges in diagnosis and management of ototoxicity.
PubMed: 29471610
DOI: 10.7874/jao.2017.00360 -
Frontiers in Neurology 2021It is well-known that aminoglycoside antibiotics can cause significant hearing loss and vestibular deficits that have been described in animal studies and in clinical... (Review)
Review
It is well-known that aminoglycoside antibiotics can cause significant hearing loss and vestibular deficits that have been described in animal studies and in clinical reports. The purpose of this review is to summarize relevant preclinical and clinical publications that discuss the ototoxicity of non-aminoglycoside antibiotics. The major classes of antibiotics other than aminoglycosides that have been associated with hearing loss in animal studies and in patients are discussed in this report. These antibiotics include: capreomycin, a polypeptide antibiotic that has been used to treat patients with drug-resistant tuberculosis, particularly in developing nations; the macrolides, including erythromycin, azithromycin and clarithromycin; and vancomycin. These antibiotics have been associated with ototoxicity, particularly in neonates. It is critical to be aware of the ototoxic potential of these antibiotics since so much attention has been given to the ototoxicity of aminoglycoside antibiotics in the literature.
PubMed: 33767665
DOI: 10.3389/fneur.2021.652674 -
Food and Chemical Toxicology : An... Feb 2020Cisplatin has dramatically improved the survival rate of cancer patients, but it has also increased the prevalence of hearing and neurological deficits in this... (Review)
Review
Cisplatin has dramatically improved the survival rate of cancer patients, but it has also increased the prevalence of hearing and neurological deficits in this population. Cisplatin induces ototoxicity, peripheral (most prevalent) and central (rare) neurotoxicity. This review addresses the ototoxicity and the neurotoxicity associated with cisplatin-based chemotherapy, providing an integrated view of the potential protective agents that have been evaluated in vitro, in vivo and in clinical trials, their targets and mechanisms of protection and their effects on the antitumor activity of cisplatin. So far, the findings are insufficient to support the use of any oto- or neuroprotective agent before, during or after cisplatin chemotherapy. Despite their promising effects in vitro and in animal studies, many agents have not been evaluated in clinical trials. Additionally, the clinical trials have limitations concerning the sample size, controls, measurement, heterogeneous groups, several arms of treatment, short follow-up or no blinding. Besides that, for most agents, the effects on the antitumor activity of cisplatin have not been evaluated in tumor-bearing animals, which discourages clinical trials. Further well-designed randomized controlled clinical trials are necessary to definitely demonstrate the effectiveness of the oto- or neuroprotective agents proposed by animal and in vitro studies.
Topics: Animals; Antineoplastic Agents; Cisplatin; Humans; Neoplasms; Neurotoxicity Syndromes; Ototoxicity; Protective Agents
PubMed: 31891754
DOI: 10.1016/j.fct.2019.111079